Method of treatment of hormone-unresponsive metastiatic prostate cancer

ABSTRACT

Prostate cancer particularly hormone-unresponsive metastatic prostate cancer, is treated by cyclophosphamide or other normally substantially inactive agent. Potentiation of the anti-cancer activity and amelioration of cyclophosphamide-associated toxicity is achieved by an initial intravenous infusion of DPPE over an approximately one hour period prior to cyclophosphamide treatment.

This application is a 371 of PCT/CA94/00676, filed on Dec. 7, 1994.

FIELD OF INVENTION

The present invention relates to the treatment of prostate cancer.

BACKGROUND TO THE INVENTION

Cancer of the prostate is now the most commonly-diagnosed cancer inmales. It is estimated that, in 1993, there will be 110,000 new cases ofprostate cancer diagnosed in the U.S. alone, while 45,000 will die fromthis disease. Prostate cancer is now the third leading cause of allcancer-specific deaths in men between the ages of 55 and 74. It isprojected that by the year 2000, a 90% increase in annual incidence ofthe disease and a 37% increase in annual mortality rates will beobserved. Although prostate cancer may be a relatively indolent neoplasmin the elderly, the overall decrease in life span in patients with thisdisease is approximately 10 years.

Improvement in the treatment of prostate cancer has centered on earlydetection; in recent years, a screening test (prostate-specific antigen,or PSA), although not entirely specific, has increased the power todiagnose this disease in asymptomatic patients. Treatment of earlyprostate cancer in men under the age of 65 has focused on radicalsurgery and/or radiotherapy, but the impact of these aggressiveapproaches on overall survival remains debatable. The approach totreatment of men over the age of 65 historically has been moreconservative, and is based on the ablation of testosterone production.This result is achieved by the administration of female hormones(estrogen) or by orchidectomy, often in combination with anti-androgenmedication. More recently, luteinizing hormone-releasing hormone (LHRH)agonists have joined the hormonal armamentarium.

Hormone manipulation often may result in significant palliation ofmetastatic prostate cancer, with improvement of bone pain and otherdisease-associated symptoms, as well as a significant fall in PSA levels(usually indicative of a decrease in tumor mass). Despite initialimprovement on hormonal treatment, a majority of patients with locallyunresectable or metastatic disease will progress and fail to respond tofurther hormonal therapies. In this large group of patients, other formsof treatment are far less effective. Radiotherapy often may relieve thesymptoms of bone pain, but is not curative. Over time, the disease willprogress with a fatal outcome.

Over the last 20 years, there have been many attempts to treatmetastatic non-hormonally responsive prostate cancer with cytotoxicchemotherapy drugs. The results have been uniformly unrewarding. Forexample, in a comprehensive review of chemotherapy trials published byEisenberger in 1985, only 131 out of 1,683 (8%) evaluable patientstreated with any form of chemotherapy had an objective response totreatment. The list of inactive agents is long and includes the drugcyclophosphamide. For example, Eisenberger's study revealed that none of57 evaluable patients responded to cyclophosphamide as a single agent.When cyclophosphamide was combined with other drugs, includingdoxorubicin, 5-fluorouracil or cisplatinum, the overall objectiveresponse rate was 20 out of 142 patients (14%). Thus, the overallresponse to cyclophosphamide alone, or in combination with other agents,was only 20 out of 199 (10%). Recently, Smith el al reported a 40%response rate (4 of 10 patients) employing very high doses ofcyclophosphamide (4.5 mg/M²) administered every 2 weeks in combinationwith granulocyte macrophage stimulating factor (GM-CSF); the latter wasadministered to counteract the severe myelosuppressive effects of thishigh dose of cyclophosphamide. Although not specifically reported, thesepatients also likely would have experienced significant nausea andvomiting and total loss of hair because of the dose of cyclophosphamideemployed.

Thus, the analysis of several studies involving over 200 patientssuggests that conventional doses of cyclophosphamide, administered aloneor in combination with other cytotoxic chemotherapy drugs, are largelyineffective in the treatment of patients with hormone-refractorymetastatic prostate cancer. Higher doses may be effective, but areassociated with severe bone marrow depression, requiring the concomitantuse of GM-CSF.

SUMMARY OF INVENTION

Surprisingly, I have recently observed in several human patients withprostate cancer that, when a conventional dose of cyclophosphamide(about 600 to 800 mg/M²) is combined with the intracellular histaminereceptor antagonist, N,N-diethyl-2- 4-(phenylmethyl)-phenoxy!ethanamine.HCl(DPPE; 240 mg/M²), a marked potentiation ofcyclophosphamide anticancer activity is observed. Conversely,cyclophosphamide-associated toxicity, including nausea, vomiting,alopecia (hair loss) and bone marrow depression, has been observed to beminimal. Thus, DPPE increases the therapeutic index of cyclophosphamidein patients with prostate cancer both by increasing the anticancerproperties of cyclophosphamide to prostate cancer cells and bydecreasing cyclophosphamide-associated host toxicity.

Accordingly, the present invention provides a novel method for thetreatment of prostate cancer employing a normally-inactivechemotherapeutic agent for prostate cancer and a compound which inhibitsnormal cell proliferation while promoting malignant cell proliferation,used in an amount sufficient to inhibit the binding of intracellularhistamine in normal cells, preferably an antagonist of intracellularhistamine binding.

In one aspect, therefore, the present invention provides a method forthe treatment of prostate cancer, which comprises administering to ahuman having prostate cancer, particularly hormone-unresponsivemetastatic prostate cancer, a compound which inhibits normal cellproliferation while promoting malignant cell proliferation, particularlya potent antagonist for intracellular histamine receptors, in an amountsufficient to inhibit the binding of intracellular histamine in normalcells, and subsequently administering to the human an effective amountof a chemotherapeutic agent which is normally substantially inactive inthe treatment of prostate cancer to effect potentiation of theanti-prostate cancer activity of said chemotherapeutic agent whileminimizing chemotherapeutic agent-associated toxicity.

GENERAL DESCRIPTION OF INVENTION

In the present invention, any compound which is a potent antagonist ofhistamine binding at the intracellular histamine receptor is useful andis administered in an amount sufficient to inhibit the binding ofintracellular histamine at the intracellular binding site (H_(IC)) innormal cells. Such compounds generally exhibit a pKi of at least about5, preferably at least about 5.5.

Specific potent compounds which are useful in the present invention arediphenyl compounds of the formula: ##STR1## wherein X and Y are eachfluorine, chlorine or bromine, Z is an alkylene group of 1 to 3 carbonatoms or ═c═o, and p are 0 or 1, R₁ and R₂ are each alkyl groupscontaining 1 to 3 carbon atoms or are joined together to form ahetero-ring with the nitrogen atom and n is 1, 2 or 3.Pharmaceutically-acceptable salts of the diphenyl compounds may beemployed.

Alternatively, the benzene rings may be joined to form a tricyclic ring,in accordance with the structure: ##STR2##

In one preferred embodiment, the group ##STR3## is a diethylamino group,although other alkylamino groups may be employed, such as dimethylamino,and, in another preferred embodiment, a morpholino group, although otherheterocyclic ring groups may be employed, such as piperazino. o and pare usually 0 when Z is an alkylene group and n may be 2. In oneparticularly preferred embodiment, Z is --CH₂ --, n is 2, o and p areeach 0 and ##STR4## is a diethylamino group. This compound, namelyN,N-diethyl-2- 4-(phenylmethyl)-phenoxy!ethanamine, in the form of itshydrochloride salt, is abbreviated herein as DPPE. In addition to amethyl group linking the benzene rings, other linking groups may beemployed, such as ═C═O. Other substitutions may be made on the benzenerings in addition to the halogen atoms, for example, an imidazole group.

The compounds used herein are potent antagonists of intracellularhistamine binding at a site designated H_(IC). Such compounds, in anintracellular histamine binding assay, generally exhibit pki values ofat least about 5, preferably at least about 5.5. For example, DPPEexhibits a pki value of 6.5. The present invention employs compoundswhich potently and preferentially bind to H_(IC).

The antagonist compound employed in the present invention isadministered to the patient by intravenous injection of a solutionthereof in an aqueous pharmaceutically-acceptable vehicle.

The antagonist compound is administered to the patient over a suitableperiod of time before administration of the chemotherapeutic agent. Thechemotherapeutic agent or a mixture of such agents may be administeredin any convenient manner consistent with its normal manner ofadministration following conventional chemotherapeutic practice, oftenby intravenous infusion of a solution thereof.

The administration of the antagonist compound to the patient prior toadministration of the chemotherapeutic agent is necessary in order topermit the antagonist to inhibit the binding of intracellular histaminein normal and malignant cells and thereby, in effect, shut downproliferation of the normal cells, but increase proliferation ofmalignant cells.

The length of time prior to administration of the chemotherapeutic agentthat the antagonist compound is administered depends on the antagonistcompound, its mode of administration and the size of the patient.Generally, the antagonist compound is administered to the patient forabout 30 to about 90 minutes, preferably about 60 minutes, prior toadministration of the at least one chemotherapeutic agent.

In general, depending on the pKi of the antagonist, the quantity ofcompound employed in humans is from about 8 to about 320 mg/M² of animalto which the antagonist compound is administered, with about 240 mg/M²being the optimal DPPE dose for gastro-intestinal, hair and bone marrowprotection. Over this dose range, the present invention is able toachieve an enhanced chemotherapeutic effect on prostate cancer cellswhile, at the same time, also protecting normal cells from damage by thechemotherapeutic agent in a wide variety of circumstances wheretraditional chemotherapy leads to damage of normal cells or tissues notinvolved in the disease process. Examples of the most common adverseeffects on normal cells which result in traditional chemotherapyinclude:

(a) the killing of, or damage to, bone marrow cells,

(b) the killing of, or damage to, normal cells lining thegastrointestinal tract, and

(c) loss of hair

In cancer-bearing animals, DPPE treatment alone modulates tumor growthwith promotion at lower doses and inhibition (cytotoxicity) at higherdoses. However, when combined with known anti-cancer drugs in the mannerdescribed herein, a marked synergistic action is observed whereby tumorsare inhibited or killed by the anti-cancer drugs. This effect has led,for example, to marked regressions or cures in some animal, includinghuman, cancers, such as sarcoma and melanoma.

As noted above, continued administration of the antagonist compoundfollowing administration of the chemotherapeutic agent at leastameliorates, and often eliminates, the side effects often associatedwith chemotherapy, including nausea, vomiting, anorexia and stomatitis,and preferably is effected herein, with the longer the period ofadministration, the more significant is the protection against the sideeffects. A daily dose of about 240 to about 1200 mg/M² of DPPE affordsmaximum bone marrow protection and synergy with chemotherapy to killcancer cells.

Such continued administration of antagonist component is mostconveniently effected by intravenous administration.

It has also been found that DPPE alone at low doses directly stimulatestumor cell growth in vivo and also increases the inflammatory responsein skin elicited by the tumor promoting phorbol ester, PMA (phorbolmyristate acetate). Several other classes of compounds, such asantidepressants, phenothiazines, triphenylethylene estrogens, histamine(H₁, H₂, H₃) antagonists, serotonin (5HT₁, 5HT₃) antagonists,β-andrenergic antagonists and imidazole analogs, also have beenidentified as producing the same results as observed for DPPE.

It now also has been found that tricyclic antidepressant drugs and thenon-tricyclic agent, fluoxetine (Prozac™), as well as H₁ -antihistamineand β-adrenergic antagonists, also compete for the binding of ³ H-DPPEand ³ H-histamine to H_(IC) in rat liver microsomes or brain membranesand, likewise, promote tumor growth.

Such compounds mimic the profiles of DPPE to inhibit normal cellproliferation but to promote malignant cell proliferation. Accordingly,these materials, at the proper dose level, could be predicted toincrease the therapeutic index of chemotherapy drugs and are includedwithin the scope of this invention.

Accordingly, in another aspect, the present invention provides a methodfor the treatment of prostate cancer wherein a compound which inhibitsnormal cell proliferation while promoting malignant cell proliferationis combined with chemotherapy agents to increase the therapeutic indexof chemotherapy drugs, in like manner to DPPE and similar potentantagonists of intracellular histamine binding as specifically describedherein.

Among the various compounds which may be employed in this aspect of thepresent invention are included:

(a) tricyclic antidepressants, such as amitriptyline, clomipramine andimipramine,

(b) non-tricyclic depressants, such as fluoxetine,

(c) phenothiazines, such as prochloroperazine, trifluoroperizine andchlorpromazine,

(d) H₁ antagonists, such as loratadine, hydroxyzine, phenyltoloxamineand astemizole,

(e) β-adrenergic agonists and antagonists, such as propanolol,

(f) serotonin (5HT₁ or 5HT₃) antagonists, such as ondansertron (5HT₃)and cyproheptadine (5HT₁),

(g) imidazoles and imidazole-like compounds, including H₂ antagonists,such as cimetidine and ranitidine, H₃ antagonists, such as thioperamideand antifungal agents, such as ketoconazole, and

(h) triphenylethylene derivatives, such as tamoxifen.

In general, the compounds which may be employed in this aspect of theinvention may have a chemical structure consisting of at least twophenyl rings, linked by a rigid third phenyl or non-phenyl ring, or by anon-rigid methyl, oxygen or other moiety, with the phenyl ring structurebeing linked by an ether, sulfhydryl or other ring structure or group toa basic alkylamine, imidazole or amino-imidazole side chain, forexample, the carboxyamide-amino-imidazole L651582.

Although this wide range of compounds may be employed to increase thetherapeutic index of chemotherapy drugs, DPPE and its direct analogs,may be significantly better agents for combination with chemotherapythan the foregoing groups of compounds, since DPPE appears to be morepotent and selective for H_(IC) and does not interact with calmodulin,protein kinase C or calcium channels and is only a weak antagonist atother common receptors, such as H₁, 5HT and D₂.

For example, DPPE does not cause serious cardiovascular effects inhumans at clinically relevant doses to enhance chemotherapy, whereas,for example, at their relevant concentrations to antagonize H_(IC), theantidepressant group of drugs and histidinol may cause cardiacarrythmias, H₁ antagonists may cause heart block and phenothiazines maycause significant hypertension.

The inhibitors to intracellular binding are employed in combination withanti-neoplastic agents which normally are ineffective in the treatmentof prostate cancer, particularly hormone-unresponsive metastaticprostate cancer, to effect potentiation of the therapeutic index of suchagent. In particular, the anti-neoplastic agent is cyclophosphamide,although others compounds useful in the present invention includeifosphamide, 5-fluorouracil, doxorubin and cis-platinum.

Such cyclophosphamide generally is used in dosage amounts which areconventional for cancer treatment or the treatment of solid tumors,usually in the range of about 600 to about 800 mg/M², although otheruseful quantities may be employed.

In one particular embodiment of the invention, the cyclophosphamide isused with DPPE as the antagonist of intracellular histamine, generallyin an amount of about 240 mg/M². At such dosage level, a markedpotentiation of cyclophosphamide anticancer activity towards prostatecancer is observed while cyclophosphamide-associated toxicity isminimized.

Preferably, the cyclophosphamide/DPPE treatment is effected by providingan intravenous infusion of an aqueous solution of DPPE over an 80 minuteperiod, with cyclophosphamide being infused over the last 20 minutes ofthe DPPE infusion. The total quantities infused during this periodcorrespond to the overall desired treatment level, as outlined above.

In general, multiple treatments by the combination of cyclophosphamideand DPPE is required to achieve remission of the prostate cancer.Treatment following the above regimen may be carried out for sixsuccessive weeks and then every two out of three weeks until the patienthas achieved a complete remission, or may be continued as required inpatients achieving partial remission or improvement, in the absence ofcomplete remission.

EXAMPLES

The invention is illustrated further by the following three casestudies:

CASE 1:

Following complaints of increased urinary frequency, a 65-year-old manwas found, in December, 1987, to have an enlarged hard prostate. Abiopsy showed infiltrating adenocarcinoma (Gleason grade not stated). Hewas treated with radical radiotherapy in April, 1988.

He remained well until August, 1990, when the PSA was elevated at 125(normal value=1 to 4). A bone scan showed soft tissue uptake of isotopein the right upper quadrant, suspicious for liver metastases. A CT scanof the abdomen on Aug. 14, 1990, showed multiple large metastases withinthe liver. Biopsy of a liver lesion showed poorly differentiatedcarcinoma, compatible with metastatic prostate cancer. He was placed onan antiandrogen, Androcur 50 mg b.i.d, and on the estrogen,stilbesterol, 0.1 mg od. The PSA decreased to 44 on July 17, and to 26on Dec. 14, 1990. Despite this, a CT scan did not show improvement. Heremained on Androcur and stilbesterol. A repeat CT scan on Mar. 22,1991, suggested some progression of the hepatic metastases. By June,1991 his PSA climbed to 60, then to 116 on Sep. 27, 1991. He began toexperience liver pain.

He was treated with bilateral orchidectomy on Nov. 8, 1991, andcommenced on a different antiandrogen, flutamide, 250 mg t.i.d. Hisliver, which had enlarged to the point where he felt uncomfortable,started to decrease. By February, 1992, his PSA decreased to 5, and hisliver decreased in size. A CT scan on Oct. 15, 1992, showed overallimprovement in the metastases; the PSA was 1.7. He continued onflutamide, but, by July, 1993, his liver started to enlarge again andhis PSA increased to 37.5.

The flutamide was discontinued. A CT scan showed extensive disease inhis liver. The PSA was in the range of 40. The liver span was 15 cm; theliver edge was easily palpable 8 cm below the costal margin. Hecommenced weekly DPPE (240 mg/M²) and cyclophosphamide (800 mg/M²), onAug. 13, 1993. Within 3 treatments, his liver pain resolved. Thealkaline phosphatase decreased from 174 on July 16 to 100 on October 7.The LDH dropped from 445 to 220, the PSA decreased from 40 μg/L at thestart of therapy to 33 μg/L on October 1st to 21 μg/L, on October 14.The liver span decreased to 13.5 cm; the liver edge was no longerpalpable. The patient was able to lay on his right side without anydiscomfort, gained approximately 2 kg within 3 months) and was able toresume work. A repeat CT scan showed a significant decrease in the sizeof the liver metastasis. He remains on weekly DPPE/cyclophosphamide andhas had no significant hair loss or bone marrow depression.

CASE 2:

This 75-year-old retired physician was well until the winter of 1992.While vacationing in California, he became very tired and felt mildlynauseated. He was found to have a PSA of approximately 1,800 andunderwent prostatic biopsy which showed a diffuse adenocarcinoma of theprostate (Gleason score=9). He was treated with monthly injections of anLHRH agonist (Zoladex) and the anti-androgen, flutamide, 250 mg t.i.d.He stopped the flutamide after 3 weeks of therapy because of sideeffects, but continued on with Zoladex, monthly by injection. The PSArapidly decreased to 3.2. He continued to do well on monthly Zoladexinjections and recommenced flutamide on a b.i.d. schedule.

By August, 1993, he started once again to feel tired and unwell. He didnot have any bone pain. The PSA level was now 568. A bone scan showeddiffuse uptake; skeletal survey showed sclerosis in his right innominatebone and in various vertebrae. He complained of easy satiety and mildnausea. Over the next six weeks, the PSA climbed to 830.

The Zoladex and flutamide were discontinued. He commenced DPPE (240mg/M²) and cyclophosphamide (800 mg/M²) therapy on Sep. 7, 1993. Within12 hours of his treatment, he developed severe diffuse bone pain in hispelvis and back, which persisted for 72 hours; he required codeine every4-6 hours for pain control. He was admitted to hospital 5 days laterbecause of persisting weakness. Following rehydration and theadministration of dexamethasone (10 mg/day) he rapidly improved. Within48 hours, he was treated again with DPPE and cyclophosphamide, withlittle if any bone pain thereafter. The PSA dropped from 830 to 250after the second treatment. He continued on DPPE/cyclophosphamide 2 outof every 3 weeks. Currently, he has no bone pain, his energy andappetite have improved, and the PSA, has declined, the most recent levelbeing 45 on Nov. 29, 1993. A repeat bone scan showed almost completeresolution of metastasis. He has had no significant hair loss or bonemarrow depression.

CASE 3:

This 61-year-old executive was diagnosed with Gleason 3-4 carcinoma ofthe prostate in October, 1989. Staging showed no spreading beyond theprostate gland. Acid phosphatase was slightly elevated at 0.91. Heunderwent radical prostatectomy; histology showed involvement of theright pelvic lymph nodes and seminal vesicles with tumor extending tothe margin of resection. The patient had post-surgical radiotherapybetween September and December 1989.

He remained reasonably well, but on May 25, 1990, the PSA (normalvalue=1-4) was found to be elevated at 5.5; it increased to 18 byAugust, 1990. In November, 1990, he started to have chest and rib pain.A bone scan showed multiple bony metastases. The patient underwentbilaterial orchidectomy and commenced flutamide 250 mg t.i.d. inOctober, 1990. By March, 1991, the PSA was 0.4 and the bone scan showedimprovement. However, in November, 1991, the PSA started to rise (6.4)but the patient continued to feel well.

By January, 1992, the PSA increased to 19. Despite the fact that he wasasymptomatic, a bone scan on Mar. 6, 1992, showed worsening of hismetastatic disease with intense focal uptake in the left sacroiliacjoint, adjacent iliac bone and multiple other sites. He remained offtherapy, but by July, 1992, began to have increasing bone pain requiringthe regular use of codeine. He developed a hard fusiform swelling behindthe right knee. The patient was started on the experimental imidazoleanalogue, R85246. He responded temporarily to this medication, butdeveloped increasingly severe bone pain, as well as proliferativechanges in his nail beds.

On Jun. 7, 1993, he started therapy with DPPE and cyclophosphamide.Following the first course of this therapy, he had a marked flare inbone pain which lasted for approximately 72 hours, accompanied by anincrease in PSA from a pretreatment level of 107 to 262. After hissecond treatment, his bone pain almost completely subsided. By the endof the third DPPE/cyclophosphamide, he was totally off his codeine andhad no further bone pain; the PSA dropped to 148 on Jul. 20, 1993. Hisnail beds resolved. Two bone scans 8 weeks apart showed stability, withno new lesions; the second scan suggested decreased uptake in variouslesions as compared to previously. The fusiform hard swelling behind theright knee decreased from 12 cm² to 7.5 cm² (CT scan). He has continuedon with DPPE/cyclophosphamide treatment, now reduced to two out of threeweeks, has continued to be free of bone pain and has been able to resumework. He has had no significant hair loss or bone marrow depression.

SUMMARY OF DISCLOSURE

In summary of this disclosure, the present invention provides a methodof treatment of prostate cancer, combining an antagonist ofintracellular histamine binding with a conventional dose of a normallyinactive agent, particularly cyclophosphamide. A specific example is thecombination of DPPE (240 mg/M²) infused intravenously over 80 minuteswith cyclophosphamide (600-800 mg/M²) infused over the last 20 minutesof the DPPE infusion. This treatment is continued weekly for six weeksand then every 2 out of 3 weeks, until the patient has achieved acomplete remission, or continued as required in patients achievingpartial remission or improvement, in the absence of complete remission.The novel method provided herein provides a significant amelioration ofcyclophosphamide-associated side effects, namely bone marrow suppressionand alopecia. Other intracellular histamine antagonists may be used incombination with cyclophosphamide, as described for DPPE. Modificationsare possible within the scope of this invention.

What I claim is:
 1. A method for the treatment of prostate cancer, whichcomprises:administering to a human having prostate cancer a compoundwhich inhibits normal cell proliferation while promoting malignant cellproliferation in an amount sufficient to inhibit the binding ofintracellular histamine in normal cells by the intravenous injection ofa solution thereof in an aqueous pharmaceutically-acceptable vehicle,and subsequently administering to said human an effective amount of achemotherapeutic agent which is normally substantially inactive in thetreatment of prostate cancer to effect potentiation of the anti-prostatecancer activity of said chemotherapeutic agent while minimizingchemotherapeutic agent-associated toxicity.
 2. The method of claim 1wherein said prostate cancer is hormone-unresponsive metastatic prostatecancer.
 3. The method of claim 2 wherein said chemotherapeutic agentcomprises cyclophosphamide, ifosphamide, 5-fluorouracil, doxorubin orcis-platinum.
 4. The method of claim 3 wherein said chemotherapeuticagent is cyclophosphamide.
 5. The method claimed in claim 4 wherein saidcompound is a potent antagonist for intracellular histamine receptors.6. The method of claim 5 wherein said potent antagonist selective forintracellular histamine receptors is a diphenyl compound of the formula:##STR5## wherein X and Y are each fluorine, chlorine or bromine, Z is analkylene radical of 1 to 3 carbons or a ═C═O group, or the phenyl groupsare joined to form a tricyclic ring, o and p are 0 or 1, R₁ and R₂ areeach alkyl groups containing 1 to 3 carbon atoms or are joined togetherto form a hetero-ring with the nitrogen atom and n is 1, 2 or 3, or apharmaceutically-acceptable salt thereof.
 7. The method of claim 6wherein the group ##STR6## is a diethylamino group, a dimethylaminogroup, a morpholino group, or a piperazino group.
 8. The method of claim6 wherein the group ##STR7## is a diethylamino group, Z is --CH₂ --,n is2, and o and p are each
 0. 9. The method of claim 8 wherein the diphenylcompound is in the form of a hydrochloride salt.
 10. The method of claim5 wherein said antagonist is administered to the animal by intravenousinfusion about 30 to about 90 minutes prior to said administration ofsaid cyclophosphamide.
 11. The method of claim 10 wherein the time isabout 60 minutes.
 12. The method of claim 11 wherein said antagonist isadministered in an amount of about 240 mg/M² of animal while saidcyclophosphamide is employed in an amount of from about 600 to about 800mg/M².
 13. The method of claim 12 wherein said administrations areeffected weekly for six successive weeks and then every two out of threeweeks until the patient has achieved complete remission, or is continuedas required in patient's achieving partial remission.
 14. The kit ofclaim 13 wherein said compound which inhibits normal proliferation is apotent antagonist for intracellular histamine receptors for component(a).
 15. The kit of claim 14 wherein said potent antagonist selectivefor intracellular histamine receptors is a diphenyl compound of theformula: ##STR8## wherein X and Y are each fluorine, chlorine orbromine, Z is an alkylene radical of 1 to 3 carbon atoms or a ═C═Ogroup, or the phenyl groups are joined to form a tricyclic ring, o and pare 0 or 1, R₁ and R₂ are each alkyl groups containing 1 to 3 carbonatoms or are joined together to form a hetero-ring with the nitrogenatom and n is 1, 2 or 3, or a pharmaceutically-acceptable salt thereof.16. The kit of claim 15 wherein the group ##STR9## is a diethylaminogroup, a dimethylamino group, a morpholino group, or a piperazino group.17. The kit of claim 15 wherein the group ##STR10## is a diethylaminogroup, Z is --CH₂ --, n is 2, and o and p are each
 0. 18. The kit ofclaim 17 wherein the diphenyl compound is in the form a hydrochloridesalt.
 19. A kit for the treatment of prostate cancer in humans,comprising:(a) a first component consisting of a compound which inhibitsnormal cell proliferation while promoting malignant cell proliferationin a dosage amount sufficient to inhibit binding of intracellularhistamine in normal cells in the human, and, separately, (b) a secondcomponent consisting of a chemotherapeutic agent which is normallysubstantially inactive in the treatment of prostate cancer in a dosageamount toxic to said prostate cancer cells when administered to thehuman subsequent to administration of said first component to the human.20. The kit as claimed in claim 19, wherein said chemotherapeutic agentis cyclophosphamide, ifosphamide, 5-fluorouracil, doxorubin orcis-platinum for component (b).
 21. The method of claim 9 wherein saidantagonist is administered to the animal by intravenous infusion over aperiod of about 30 to about 90 minutes prior to administration of saidcyclophosphamide by intravenous infusion while intravenous infusion ofsaid antagonist is maintained.
 22. The method of claim 21 wherein saidintravenous infusion of said antagonist is effected for a total of about80 minutes to administer a total amount of about 240 mg/M² of saidantagonist while said intravenous infusion of cyclophosphamide iseffected over the last about 20 minutes of said intravenous infusion ofsaid antagonist to administer about 600 to 800 mg/M² ofcyclophosphamide.